The present invention relates to a novel process for peptide synthesis, by the addition of amino acids to the activated C-terminus of a peptide chain. Peptide synthesis is central to the manufacture of many drugs and medicaments. Peptides or derivatives thereof are used for the treatment of many disorders from antibiotics to anticancer agents. Therefore improving peptide synthesis and the yield of peptide produced by chemical synthesis has been the focus of much research in recent years.
Chemical synthesis of proteins or peptides has been a particular focus in the art. The chemical synthesis of proteins or peptides allows the production of purified peptides of specific amino acid sequence. It also allows the production of truncated sequences of amino acids and allows the introduction of non-natural amino acid derivatives.
Proteins are produced in nature by the stepwise condensation of amino acid monomers on a ribosome. Synthesis of the protein begins from the N-terminal residue and grows towards the C-terminus. The conventional approach to peptide synthesis has concentrated on extension at the N-terminus of a growing peptide. This approach forms the basis of conventional solid phase peptide synthesis. Peptide synthesis solely by extension from the N-terminus is limiting as it renders any peptide synthesis linear in nature, rather than convergent. This can severely increase overall length of synthesis, increase operational time and decrease overall yield with consequent possibilities for the loss of stereochemical fidelity.
To overcome the problems associated with N-terminal extension of a peptide, it could be envisaged that the synthesis could instead provide extension of a peptide from the C-terminal. However, attempts at peptide synthesis in the N to C direction have been generally unsuccessful due to epimerisation of the carboxy-terminal amino acid residue. This is due to the tendency of carboxy-terminal-activated acylamino acids and peptides to form oxazolones. As illustrated below, the formation of the oxazolone allows rapid racemisation of the alpha-position of the terminal amino acid residue of the acyl amino acid or peptide.

This racemisation prevents the production of stereochemically homogeneous peptides by C-terminus extension.
It will be appreciated that the production of isomerically pure compounds is a particular requirement in the art. Any method which results in the production of a mixture of isomers will require the use of time consuming and expensive purification steps to separate the isomers. Chiral compounds which are administered to humans or animals are usually required in enantiomerically pure form. The presence of unwanted isomers even in low concentrations can reduce the potency of the compound and can produce unwanted and in some cases disastrous side effects. The incorporation of an unwanted enantiomer into a peptide chain (for example the incorporation of a D-amino acid into a peptide composed of L-amino acids) may disrupt the folding and/or 3D shape of the peptide, thus resulting in a peptide which may have unpredictable binding activities and/or biological properties. The production of enantiomerically pure peptides is therefore of paramount importance.
Various attempts have been made to overcome this problem. Iorga, B and Campagne, J-M (2004, Synlett 10, 1826-1828) attempted to reduce the degree of epimerisation by improving the rate of peptide bond formation over the rate of oxazolone formation, so that peptide bond formation was the predominant reaction. However, this method does not entirely prevent the formation of the oxazolone and therefore epimerisation at the carboxy-terminal activated amino acid residue occurs. Native chemical ligation has been developed to overcome problems of carboxy-terminal extension but is ordinarily restricted to couplings in which the amino-terminal partner is an assisting cysteine residue and is not applicable to general techniques of automated solid phase peptide synthesis. The application of native chemical ligation to other amino-terminal amino acids has had very limited success.
The present invention provides a new method of producing a peptide by extension from the activated carboxy-terminus of an acyl amino acid residue. This new method overcomes the problems of epimerisation of the terminal amino acid residue during the coupling step. The present invention therefore allows the production of peptides by a convergent approach and provides a new method for the production of potentially biologically important compounds instead of the linear repetitive amino terminal extension approach currently used.
The first aspect of the present invention provides a process comprising substitution of an acceptor molecule comprising a group —XC(X)— (preferably —X(CO)—) wherein each X is independently O, S or NR8, where R8 is hydrogen, aliphatic group or an aromatic group, preferably hydrogen, C1-6 alkyl, C6-12 aryl, with a nucleophile, wherein the acceptor molecule is cyclised such that said nucleophilic substitution at —XC(X)— occurs without racemisation. The acceptor molecule is preferably a cyclised amino acid or derivative thereof. In particular, the acceptor molecule is a compound of formula (II):
wherein each X is O, S, or NR8, where R8 is as defined above;R2 is independently selected from an aliphatic group, such as a C1-10 branched or straight chain alkyl group, or an aromatic group, such as C5-12 heteroaryl group or C6-12 aryl group, each optionally substituted with a group including, for example, OR13, SR13, N(R13)2, CO2R13, CON(R13)2, SO2R12, SO3R12, phenyl, imidazolyl, indolyl, hydroxyphenyl or NR13C(═NR13)N(R13)2;R3 is as defined for R2 or is hydrogen,
or a group —C(R1′) (R9)—N(R10)(R11);wherein R1′ is independently selected from an aliphatic group such as C1-10 branched or straight chain alkyl group, an aromatic group, such as C5-12 heteroaryl group or C6-12 aryl group, each optionally substituted with a group such as OR13, SR13, N(R13)2, CO2R13, CON(R13)2, SO2R12, SO3R12, phenyl, imidazolyl, indolyl, hydroxyphenyl or NR13C(═NR13)N(R13)2;wherein when Y is NR8, R8 and R1′ can together form a 4 to 7 membered ring, optionally substituted with a group such as CO2R13, OR13, SR13, N(R13)2, CO2R13, CON(R13)2, C1-10 alkyl or C6-12 aryl, wherein said ring can be fully, partially or unsaturated, and wherein the ring may contain one or more additional heteroatoms selected from O, S or N;R12 is hydrogen, C1-6 alkyl, C6-12 aryl or N(R13)2, wherein each occurrence of R13 is independently hydrogen, C1-6 alkyl or C6-12 aryl, and R4′ is a carboxyl protecting group or hydrogen;R9 and R10 are independently hydrogen or a group as defined for R1′;R11 is hydrogen or an amino protecting group preferably selected from a benzyloxycarbonyl group, a t-butoxycarbonyl group, a 2-(4-biphenylyl)-isopropoxycarbonyl group, a fluorenylmethoxycarbonyl group, a triphenylmethyl group and/or a 2-nitrophenylsulphenyl group;or R9 and R10 or R10 and R11 or R1′ and R10 or two R13 can together form a 4 to 7 membered ring, optionally substituted with a group such as CO2R13, OR13, SR13, N(R13)2, CO2R13, CON(R13)2, C1-10 alkyl or C6-12 aryl, wherein said ring can be fully, partially or unsaturated, and wherein the ring may contain one or more additional heteroatoms selected from O, S or N;Y is O, S or NR8, where R8 is as defined above;or YR4′ is R3;R5 is an aromatic group such as C6-12 aryl, C5-12 heteroalkyl or an aliphatic group such as C1-8 branched or straight chain alkyl optionally substituted with a group such as OR13, SR13N(R13)2, CO2R13, CON(R13)2, phenyl, imidazolyl, indolyl, hydroxyphenyl or NR13C(═NR13)N(R13), or a linker for attachment of formula (II) to a resin or a linked resin;n is 0, 1, 2 or 3 and m is an integer, such as an integer selected from 1-100.
The nucleophilic substitution of the acceptor molecule preferably occurs without epimerisation.
Preferably, the process is carboxy terminal extension of an acceptor molecule, for example an amino acid or peptide. The invention therefore provides a process for the synthesis of a peptide or a peptide analog by carboxy terminal extension, by the addition of a nucleophile to an acceptor molecule, such as a compound of formula (II).
There is further provided a process for the production of a compound of formula (I)
comprising reaction of a compound of formula (II) or (II′) (above) with a compound of formula (III)HY—R7  (III)wherein the variables are defined as above;preferably X is O, S, or NR8, where R8 is as defined above; Y is O, S or NH;R2 is independently selected from a C1-10 branched or straight chain alkyl group, C5-12 heteroaryl group or C6-12 aryl group, optionally substituted with OR13, SR13, N(R13)2, CO2R13, CON(R13)2, SO2R12, SO3R12, phenyl, imidazolyl, indolyl, hydroxyphenyl or NR13C(═NR13)N(R13)2;R3 is as defined for R2 or is hydrogen, or a group
or a group —C(R1′)(R9)—N(R10)(R11);wherein R1′ is hydrogen or as defined from R1 below; Y is as defined above and R4 is as defined for R4 below;R12 is hydrogen, C1-6 alkyl, C6-12 aryl or N(R13)2, wherein each occurrence ofR13 is independently hydrogen, C1-6 alkyl or C6-12 aryl,R9 and R10 are independently hydrogen or a group as defined for R1′:or R9 and R10 can together form a 4 to 7 membered ring, optionally substituted with CO2R13, OR13, SR13, N(R13)2, CO2R13, CON(R13)2, C1-10 alkyl or C6-12 aryl, wherein said ring can be fully, partially or unsaturated, and wherein the ring may contain one or more additional heteroatoms selected from O, S or N,R11 is hydrogen or an amino protecting group preferably selected from a benzyloxycarbonyl group, a t-butoxycarbonyl group, a 2-(4-biphenylyl)-isopropoxycarbonyl group, a fluorenylmethoxycarbonyl group, a triphenylmethyl group and/or a 2-nitrophenylsulphenyl group;R5 is an aromatic group, such as C5-12 aryl, C5-12 heteroalkyl or an aliphatic group, such as C1-8 branched or straight chain alkyl optionally substituted with OR13, SR13, N(R13)2, CO2R13, CO N(R13)2, phenyl, imidazolyl, indolyl, hydroxyphenyl or NR13C(═NR13)N(R13)2 or a linker for attachment of formula (II) to a resin or a linked resin; R6 is hydrogen or
wherein R5 and X are as defined above;R7 is a chiral, substituted methylene, such as a group
or is independently selected from an aliphatic group such as a C1-10 branched or straight chain alkyl group or an aromatic group, such as a C6-12 aryl group, optionally substituted with OR13, SR13, N(R13)2, CO2R13, CON(R13)2, SO2R12, SO3R12, phenyl, imidazolyl, indolyl, hydroxyphenyl or NR13C(═NR13)N(R13)2,or wherein R7 and Y together form a 4 to 7 membered ring, optionally substituted with a group such as OR13, SR13, N(R13)2, CO2R13, CON(R13)2, SO2R12, SO3R12, phenyl, imidazolyl, indolyl, hydroxyphenyl or NR13C(═NR13)N(R13)2, wherein said ring can be fully, partially or unsaturated, and wherein the ring may contain one or more heteroatoms in addition to Y, selected from O, S or N;wherein R1 is R1′ or is independently selected from an aliphatic group such as C1-10 branched or straight chain alkyl group, or an aromatic group such as C5-12 heteroaryl group or C6-12 aryl group optionally substituted with a group such as OR13, SR13, N(R13)2, CO2R13, CON(R13)2, SO2R12, SO3R12, phenyl, imidazolyl, indolyl, hydroxyphenyl or NR13C(═NR13)N(R13)2,and R4 is R4′ or a carboxyl protecting group or hydrogen; n is 0, 1, 2 or 3 and m is an integer such as a value selected from 1-100 and when n=0, R6 is H.
The inventors have surprisingly found that activation of an amino acid or peptide via a cyclic compound as exemplified in formula (II) prevents the formation of an oxazolone thereby allowing the condensation of a compound of formula (III) without concommitant epimerisation. The invention therefore provides peptides via C-terminus extension, said peptides being produced in an enantiomerically and diastereochemically pure form.
The use of activated cyclic N-acyl amino acids, peptides or derivatives thereof eliminates oxazolone formation and associated epimerisation. The use of cyclic activated intermediates in the present invention provides an improved method of peptide synthesis via carboxy-terminal extension.
Therefore, rather than merely reducing the probability of epimerisation occurring, as has been attempted in the prior art, the process of the present invention does not permit epimerisation and therefore guarantees the production of a peptide of correct stereochemistry as the activated carboxyl terminus is held in a cyclic template such that the adjacent amide cannot form the oxazolone.
In accordance with usual practice, * denotes a stereocenter (asymmetric center). Where a compound contains a stereocenter (whether marked in the present application with * or not) the stereochemistry of the asymmetric centers may be in the R or S configuration. The compounds of the present application can be provided in enantiomerically pure form or as a mixture of isomers (including a racemic mixture). Preferably, the compounds of the present inventions are provided in an enantiomerically pure form. The present invention allows maintenance of the desired stereochemistry throughout the synthetic pathway. Thus wherein Y is NH, the amino acids to be attached may be of U or D configuration as required.
Preferably R1 and R2 are independently selected from C1-4 branched or straight chain alkyl optionally substituted with OR13, SR13, N(R13)2, CO2R13, CON(R13)2, phenyl, imidazolyl, indolyl, hydroxyphenyl or NR13C(═NR13)N(R13)2, preferably optionally substituted with OH, SH, NH2, CO2H, CONH2, phenyl, imidazolyl, indolyl, hydroxyphenyl or NH(C═NH)NH2.
More preferably, R1 and R2 are independently selected from C1 alkyl optionally substituted with OH, SH, CO2H, CONH2, phenyl, imidazolyl, indolyl or hydroxyphenyl; C2 alkyl optionally substituted with OH, CO2H, CONH2 or SCH3; C3 alkyl optionally substituted with NHC(═NH)NH2; or C4 alkyl optionally substituted with NH2.
The integer, m is preferably 1-50, more preferably 1 to 30, most preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. The integer n is preferably 0 or 1.
When X is NR, R is preferably Ci-4 alkyl, more preferably methyl, ethyl, n-propyl, iso-propyl, n-butyl or tert-butyl, phenyl, naphthyl, anthracenyl or phenanthracenyl, more preferably phenyl or hydrogen.
R3 may also be substituted pipecolic acid or derivative thereof, α-alkoxy-α-amino acids, cc, α-diamino acids, β-substituted dehydroamino acids, canavanine, cysteinesulphonamide, homocysteinesulphonamide, γ,δ-unsaturated amino acids. substituted 4-hydroxyprolines, 4-hydroxtyornithines, imino sugars, Fmoc-BPC—OH, Fmoc-TPG-OH and Fmoc-CAA-OH, or (5)-3,5-dihydroxyphenylglycine.
It will be appreciated by a person skilled in the art that amino acids, hydroxy acids and derivatives thereof contain functional groups which require protection. In particular it is known in the art to protect the amino terminus, the carboxyl terminus and/or the side chains of an amino acid or peptide (for example wherein R1 or R2 is C2CO2H or CH2CH2OH). Examples of such protection are well known in the art. In particular the amino terminus of an amino acid may be protected by one or more of a benzyloxycarbonyl group, a t-butoxycarbonyl group, a 2-(4-biphenylyl)-isopropoxycarbonyl group, a fluorenylmethoxycarbonyl group, a triphenylmethyl group and/or a 2-nitrophenylsulphenyl group. The carboxyl group can be protected by one or more of an ester group especially a methyl, ethyl, benzyl, t-butyl or phenyl ester. Thus R4 is preferably methyl, ethyl, benzyl, t-butyl or phenyl.
Conditions for the removal of the protecting groups discussed above are well known in the art. The protecting groups may be removed after each coupling reaction (for example, the carboxyl protection) or alternatively at the end of the synthesis (for example, the side chain protection and/or the N-terminal group).
In a particular feature of the first aspect, the invention provides a process for production of a compound of formula (Ia)
comprising reacting a compound of formula (IIa) (above)with a compound of formula (III) HY—R7:Wherein the groups Y, X, R2, R3, R5, and R7 are as defined above.In an alternative feature of the first aspect, the invention provides a process for production of a compound of formula (Ib)
comprising reacting a compound of formula (IIb)
with a compound of formula (III) HY—R7 wherein the groups Y, X, R2, R3, R5 and R7 are as defined above for compounds (I), (II) and (III).
The N and the terminal ester of formula (I), (Ia) or (Ib) can be unmasked by processes known in the art. for example, sodium liquid ammonia in the presence of an alcohol when R1=phenyl and R4=t-butyl. Alternatively, the ester can be further derivatized, including for example, amidation.
The nucleophilic substitution of the acceptor molecule of the first aspect of the invention can be carried out using reaction conditions known in the art. In some circumstances, for example where the nucleophile and/or the acceptor molecule are sterically hindered it may be necessary for example to use high pressure such as around 19-20 bar, and/or longer reaction times such as 12-72 hours, preferably 24-48 hours. Alternatively, the reaction can be carried out in the presence of a reagent such as AlMe3. When the substitution is carried out on the solid phase, the reaction can be promoted by the use of an excess of nucleophile.
The invention further relates to a process for the production of a compound of formula (II) (above) by the reaction of a compound of formula (IV)
with a compound of formula (V) Z—CO—R3 wherein Z is any substituent capable of being involved in peptide bond formation preferably hydroxide, halide or azide, and R2, R3, R5, X and n are as defined above. It will be appreciated that when R3 is a protected peptide, subsequent N-terminus extension may be carried out using peptide synthesis methods known in the art, such as deprotection and further peptide bond formation.
The process of the present invention can particularly be used for the production of cyclic compounds, for example cyclic peptides.
It will be appreciated that when R3 is C(R1′)(R9)—N(R10)(R11), the compound of formula (II) can be reacted with one or more compounds of formula (V) in a stepwise direction.
The present invention therefore encompasses a compound of formula (VII);
wherein the variables are described above, preferably m is an integer of 1 to 50, preferably 1 to 30, more preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17. 18, 19 or 20; and R1′, R2, R5, R9, R10, R11, X and n are as defined above.
The compound of formula (VII) can be used in a process for the formation of a compound of formula (I) (illustrated below as (Ic));
when R14 is —[C(O)—C(R9)(R1′)—N(R10)—]m—(R11) and R1′, R2, R6, R7, R9, R10, R11, m, X and Y are as described above, comprising reaction of a compound of formula (VII) with a compound of formula (III) as described above. The compound of formula (I) can then be converted into a compound of formula (VI) by removal of the group R6 as described below. For the compound of formula (VII) and compounds of formula (I) or (VI) obtained therefrom, the substituents R1 and R9 can be replaced by a group (═R1) wherein R1 is as described above.
It will be appreciated that when m is 3 or more, and R10 and R11 are hydrogen, condensation can occur at the X—C(O)— functionality of the compound of formula (VII) to form a cyclised compound of formula (VIII);
wherein the variables are as defined above.
The present invention therefore provides a compound of formula (VIII). In addition, the invention provides a process for the production of a compound of formula (VIII) comprising cyclisation of a compound of formula (VII) wherein m is 3 or more. Reaction of the compound of formula (VIII) under reducing conditions (for example in the presence of lithium and liquid ammonia) results in the formation of a compound of formula (IX);
wherein R1′, R2, R9, X and m are as defined above.
The present invention therefore provides a compound of formula (IX) and a process for the production of a compound of formula (IX) comprising the reduction of a compound of formula (VIII).
It will be appreciated that the process of the present invention can be carried out in solution. Alternatively, a compound of formula II may be attached to a resin via the group R5 and the peptide synthesis carried out via solid phase peptide synthesis. When R5 is a linker it can be a group OR13, N(R13)2, CO2R13 or Se, or an alkyl group having 1 to 4 carbons or a C6-12 aryl group, said alkyl and aryl groups being optionally substituted with OR13, N(R13)2, CO2R13 or SR13. Alternatively, part of the synthesis may be carried out on the solid phase and part in solution.
The compound of formula II can be attached to and removed from a resin using methods known in the art.
Solid phase peptide synthesis using the process of the present invention may be carried out by using procedures attaching the carboxy-terminal to any resin known in the art. Examples of suitable resins include Wang, Merrifield, polyimide, 2-chlorotrityl, Rink, Knorr, DCHD, PAL and any other known in the art. Solid phase coupling partners such as BOP, PyBOP and DCC may be used, as well as any other suitable coupling partners known in the art.
A further feature of the first aspect is a process for the production of a compound of formula (VI)
from formula (I)
by the removal of R6 by any method known in the art, wherein X, Y, R2, R3, R6 and R7 are as defined above. It will be appreciated that when R6 is hydrogen, the compound of formula (I) corresponds to the compound of formula (VI).
In particular, the removal of the group R6 may be carried out under reducing conditions such as under Birch conditions (i.e. with lithium and liquid ammonia). As it will be appreciated by the skilled person, the peptide produced by the process of the first aspect may be post modified by any suitable method known in the art. A second aspect of the present invention relates to the compounds described herein, including a compound of formula (II)
wherein X is O, S or NR8, where R8 is C1-6 alkyl, C6-12 aryl or hydrogen R2 is independently selected from a C1-10 branched or straight chain alkyl group, C5-12 heteroaryl group or C6-12 aryl group, optionally substituted with OR13, SR13, N(R13)2, CO2R13, CON(R13)2, SO2R12, SO3R12, phenyl, imidazolyl, indolyl, hydroxyphenyl or NR13C(═NR13)N(R13)2; R3 is as defined for R2 or is hydrogen, or a group
or a group —C(R1′)(R9)—N(R10)(R11) wherein R1 is independently selected from a C1-10 branched or straight chain alkyl group, C5-12 heteroaryl group or C6-12 aryl group optionally substituted with OR13, SR13, N(R13)2, CO2R13, CON(R13)2, SO2R12, SO3R12, phenyl, imidazolyl, indolyl, hydroxyphenyl or NR13C(═NR13)N(R13)2 wherein when Y is NR8, R8 and R1′ can together form a 4 to 7 membered ring, optionally substituted with CO2R13, OR13, SR13, N(R13)2, CO2R13, CON(R13)2, C1-10 alkyl or C6-12 aryl, wherein said ring can be fully, partially or unsaturated,and wherein the ring may contain one or more heteroatoms selected from O, S or N;R12 is hydrogen, C1-6 alkyl, C6-12 aryl or N(R13)2, wherein each occurrence of R13 is independently hydrogen, C1-6 alkyl or C6-12 aryl, R9 and R10 are independently hydrogen or a group as defined for R1; or R9 and R10 can together form a 4 to 7 membered ring, optionally substituted with CO2R13, OR13, SR13, N(R13)2, CO2R13, CON(R13)2, C1-10 alkyl or C6-12 aryl, wherein said ring can be fully, partially or unsaturated, and wherein the ring may contain one or more heteroatoms selected from O, S or NR11 is hydrogen or an amino protecting group preferably selected from a benzyloxycarbonyl group, a t-butoxycarbonyl group, a 2-(4-biphenylyl)-isopropoxycarbonyl group, a fluorenylmethoxycarbonyl group, a triphenylmethyl group and/or a 2-nitrophenylsulphenyl group; R1 is independently selected from C1-10 branched or straight chain alkyl optionally substituted with OR13, SR13, N(R13)2, CO2R13, CO N(R13)2, phenyl, imidazoyl, indolyl, hydroxyphenyl or NR13C(═NR13)N(R13)2 and R4′ is a carboxyl protecting group or hydrogen and n is 0, 1, 2 or 3, m is 1-100; and R5 is a linker for attachment of formula (II) to a resin, a linked resin, or C6-12 aryl, C5-12 heteroalkyl or C1-8 branched or straight chain alkyl optionally substituted with OR13, SR13, N(R13)2, CO2R13, CON(R13)2, phenyl, imidazolyl, indolyl, hydroxyphenyl or NR13C(═NR13)N(R13)2; wherein when X═O, and R5 is phenyl, n is not 0 or 1.
Preferably R1 and R2 are independently selected from C1-4 branched or straight chain alkyl optionally substituted with OR13, SR13, N(R13)2, CON(R13)2, phenyl, imidazolyl, indolyl, hydroxyphenyl or NR13C(═NR13)N(R13)2. More preferably R1 and R2 are independently selected from C1 alkyl optionally substituted with OR13, SR13, CO2R13, CO N(R13)2, phenyl, imidazolyl, indolyl or hydroxyphenyl; C2 alkyl optionally substituted with OR13, CO2R13, CON(R13)2 or SCH3; C3 alkyl NR13C(═NR13)N(R13)2 or C4 alkyl optionally substituted with N(R13)2.
As set out above, R4 is a carboxyl protecting group, such as an ester group. In particular R4 is preferably methyl, ethyl, benzyl, t-butyl or phenyl. When R5 is a linker it can be OR13, N(R13)2. CO2R13 or SR13 or an alkyl group having 1 to 4 carbons or a C6-12 aryl group, wherein the alkyl group and/or aryl group can be substituted with one or more of OR13, N(R13)2, CO2R13 or SR13.
The integer, m is preferably 1-50, more preferably 1 to 30, most preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. The integer n is preferably 0 or 1.
When X is NR8, R8 is preferably C1-4 alkyl, more preferably methyl, ethyl, n-propyl, iso-propyl, n-butyl or tert-butyl, phenyl, naphthyl, anthracenyl or phenanthracenyl, more preferably phenyl or hydrogen.
R13 is preferably hydrogen or C1-4 alkyl, more preferably methyl, ethyl, n-propyl, iso-propyl, n-butyl or tert-butyl.
For the purposes of this invention, alkyl relates to both straight chain and branched, saturated or unsaturated alkyl radicals having, for example, 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms and most preferably 1 to 4 carbon atoms including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl n-pentyl, n-hexyl, n-heptyl, n-octyl. Alkyl therefore relates to a group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more carbon atoms. The term alkyl also encompasses cycloalkyl radicals of 3 to 12 carbon atoms, preferably 4 to 8 carbon atoms, and most preferably 5 to 6 carbon atoms including but not limited to cyclopropyl, cyclobutyl, CH2-cyclopropyl, CH2-cyclobutyl, cyclopentyl or cyclohexyl. Cycloalkyl groups may be optionally substituted or fused to one or more carbocyclyl or heterocyclyl group. Haloalkyl relates to an alkyl radical preferably having 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms substituted with one or more halide atoms for example CH2CH2Br, CF3 or CCl3. An alkyl group may be optionally interrupted by one or more O, S or NH groups, preferably one or more O atoms to form an alkoxy group. An alkyl group may be optionally interrupted by one or more double or triple bonds to form a group including but not limited to ethylene, n-propyl-1-ene, n-propyl-2-ene, isopropylene, ethynyl, 2-methylethynyl etc.
“Aryl” means an aromatic 6 to 12 membered hydrocarbon or heteroaryl containing one ring or being fused to one or more saturated or unsaturated rings including but not limited to phenyl, naphthyl, anthracenyl or phenanthracenyl. “Heteroaryl” means an aromatic 5 to 12 membered aryl containing one or more heteroatoms selected from N, O or S and containing one ring or being fused to one or more saturated or unsaturated rings including but not limited to furan, imidazole, indole, oxazole, purine, pyran, pyridine, pyrimidine, pyrrole, tetrahydrofuran, thiophene and triazole. The aryl and heteroaryl groups can be fully saturated, partially saturated or unsaturated.
Halogen means F, CI, Br or I, preferably F.
A third aspect of the invention relates to the use of a compound of formula (II) as defined in the first and/or second aspects of the invention in asymmetric synthesis.
All preferred features of each of the aspects of the invention apply to all other aspects mutatis mutandis.
The present invention will now be illustrated by reference to one or more of the following non-limiting examples: